Many human neurodegenerative diseases are poorly understood and untreatable, including Parkinson's (PD), Alzheimer's and Huntington's diseases. For some familial forms, mutations in specific genes are known, allowing pathology to be modeled in simpler systems in order to define mechanisms and pioneer novel treatments. Toward this end, we applied the power of fly genetics to the problem of neurodegeneration by developing models for human disease in Drosophila. Here, we propose to further characterize mechanisms of alpha-synuclein (alpha-syn) associated loss of dopaminergic (DA) neuron integrity, and to study a newly-identified PD-like disorder gene, DJ-1, and its role in protection from oxidative stress. Mutations in alpha-syn are pathogenic for hereditary PD, and wild-type alpha-syn is the major protein component of the pathological aggregates called Lewy bodies that characterize sporadic PD and other synucleinopathies. In Drosophila, expression of alpha-syn compromises the integrity of DA neurons. To further investigate this, in Aim 1 we propose to generate modified forms of alpha-syn and then characterize in detail their toxicity in vivo. Modifications of interest include new hereditary mutations, truncation, and phosphorylation, which are associated with PD or have striking effects on alpha-syn fibrillization in vitro. In Aim 2, given strong links between environmental toxins and development of PD, we will expand our studies of Drosophila models to the detailed characterization of a new PD-like disorder gene, DJ-1. Preliminary studies reveal that null mutation of fly DJ-1 homologues strikingly enhances sensitivity to select oxidative toxins associated with PD, including paraquat and rotenone. Since oxidative damage is thought to be critically involved in both genetic and sporadic forms of PD, study of DJ-1 homologues will reveal new insight into these links. In Aim 3, we will apply the power of Drosophila genetics to address conserved features of alpha-syn and DJ-1-associated pathology, in order to pioneer new approaches to understand and treat human neurodegeneration.